The Clinical Pharmacokinetics of Itraconazole: An Overview

Abstract

Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungaI fl uconazole.The pharmacokinetics of itraconazole in man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day and a biotransformation into a large number of metabolites. One of them, hydroxy-itraconazole, is antifungally active and explains why antifungal plasma levels, when measured by bioassay, are about three times the itraconazole levels measured by a specific HPLC-method.Distribution studies have shown that therapeutically active levels of itraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for 3 weeks in the stratum corneum of the skin after treatment has been stopped. Unlike fluconazole, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high eficacy and safety of itraconazole in patients with various mycotic infections. New pharmaceutical formulations are being explored in order to broaden the application field of itraconazole to intravenous and oral therapy of patients with malabsorption.

Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation

“…These results suggest an improvement of the bioavailability of itraconazole in oral solution. This is also evident when comparing our data with those provided by Heykants et al 15 and Kintzel et al 16 in allogeneic BMT patients treated with itraconazole 200 mg daily as capsules or itraconazole suspension formulations where itraconazole concentrations were extremely low.…”

“…On those days, two samples were taken: one before itraconazole intake (minimum concentration = C min ) and one 4 h later (maximum concentration = C max ), corresponding to the peak. 7 Plasma samples were assayed for ITRA and its active metabolite OH-ITRA by a reverse phase HPLC method. 10 The lower limit of quantification was 50 ng/ml.…”

“…This effective level could be estimated from the effective plasma levels of unchanged ITRA (Ϸ250 ng/ml) 4,6 and metabolic ratio in human plasma between ITRA and OH-ITRA ([OH-ITRA]/[ITRA] Ϸ2). 7 However the capsule formulation is of limited use in allogeneic BMT: its bioavailability is reduced when administered under fasting conditions and when coadministered with antacids. 8 Itraconazole oral solution is a new formulation where ITRA is solubilized in an aqueous solution via a hydroxypropyl-␤-cyclodextrin vehicle.…”

Determination of Antifungal Activities in Serum Samples from Mice Treated with Different Antifungal Drugs Allows Detection of an Active Metabolite of Itraconazole

“…4) The spot for the possible active metabolite was detected after a longer sampling time than the itraconazole spot. The conversion of itraconazole to an active metabolite, hydroxy-itraconazole, has also been confirmed in humans (8,9). The antifungal titer obtained in our results suggested that the pharmacodynamic activity of the metabolite was comparable to that of itraconazole in mice as well as humans (4,13,23,31).…”

“…We currently do not have information on whether the active metabolite in mice was hydroxy-itraconazole (8,9). Further investigation including the identification of the active metabolite in mice would lead to a better understanding of the in vivo activity and serum antifungal titer of itraconazole.…”